GENETIC-VARIATION IN LIPOPROTEIN (A) LEVELS IN FAMILIES ENRICHED FOR CORONARY-ARTERY DISEASE IS DETERMINED ALMOST ENTIRELY BY THE APOLIPOPROTEIN (A) GENE LOCUS

Lipoprotein (a) (Lp[a]) is a cholesterol-rich lipoprotein resembling L DL but also containing a large polypeptide designated apolipoprotein ( a) (apo[a]). Its levels are highly variable among individuals and, in a number of studies, are strongly correlated with the risk of coronary artery disease (CAD). In an effort to determine which genes control L p(a) levels, we have studied 25 multiplex families (comprising 298 mem bers) enriched for CAD. The apo(a) gene was genotyped among the famili es, using a highly informative pulse-field gel electrophoresis procedu re. In addition, polymorphisms of the gene for the other major protein of Lp(a), apolipoprotein B (apoB), were examined. Quantitative sib-pa ir linkage analysis indicates that apo(a) is the major gene controllin g Lp(a) levels in this CAD population (P = .001; 99 sib pairs), wherea s the apoB gene demonstrated no significant quantitative linkage effec t. We estimate that the apo(a) locus accounts for less than or equal t o 98% of variance of Lp(a) serum levels. Approximately 43% of this var iation is explained by size polymorphisms within the apo(a) gene. Thes e results indicate that the apo(a) gene is the major determinant of Lp (a) serum levels not only in the general population but also in a high -risk CAD population.